WO2001068767A1

WO2001068767A1 - Dispersion comprising a non-ionic emulsifier

Info

Publication number: WO2001068767A1
Application number: PCT/EP2001/001108
Authority: WO
Inventors: Christian Meier; Johanna Eisele; Michael Schnabel; Klaus Schultes; Stefan Grimm; Hans-Ulrich Petereit; Thomas Süfke
Original assignee: Röhm GmbH & Co. KG
Priority date: 2000-03-10
Filing date: 2001-02-02
Publication date: 2001-09-20
Also published as: PL350610A1; US20030060381A1; DE50104475D1; PL199225B1; ATE282067T1; US6998140B2; DE10011447A1; CA2386932A1; EP1200521B1; JP4944334B2; AU3023201A; JP2003526724A; CA2386932C; ES2228799T3; DK1200521T3; EP1200521A1

Abstract

The invention relates to a dispersion that is suitable for the use as a coating and binding means for forms of medicaments. The inventive dispersion has a solids content of 10 to 70 wt. % and consists of a) 90 to 99 wt. % of a methacrylate copolymer which consists of at least up to 90 wt. % of (meth)acrylate monomers and detects a glass temperature Tg of 20 °C to +20 °C according to the DSC method, whereby said monomers have neutral radicals. Said dispersion also consists of 1-10 wt. % of a non-ionic emulsifier having an HLB value of 15.2 to 17.3.

Description

Dispersion with non-ionic emulsifier

The invention relates to the field of dispersions and their use as coating and binding agents for pharmaceutical forms.

State of the art

The use of so-called neutral methacrylate copolymers, that is to say methacrylate copolymers, which predominantly consist of (meth) acrylate monomers with neutral residues, such as methyl methacrylate or ethyl acrylate, as coating and binders for pharmaceutical forms with delayed release of active ingredient has long been known.

Uses in mixtures with anionic dispersions are described for. B. in EP-A 152 038, EP-A 208 213 or EP-A 617 972.

The neutral methacrylate copolymers are used today preferably as dispersions. Dispersions of this type are produced by emulsion polymerization and therefore contain an emulsifier which, due to their production, also effects the stability of the dispersion obtained as such. In the finished pharmaceutical form, the emulsifier contained also influences the active ingredient release characteristics.

The choice of suitable emulsifiers is very limited due to the intended use in medicinal products and because the copolymers have no or only low charges due to the monomer composition. Göpferich and Lee describe in "The influence of endogenous surfactant on the structure and drug-release properties of Eudragit NE30D-matrices", Journal of Controlled Release 18 (1992), pp. 133-144, that an emulsifier of the type contained in the dispersion Nonylphenol causes drug release problems from coated dosage forms. The authors describe an anisotropic structure in copolymer films obtained from the dispersion. This results in phase separation and crystallization of the emulsifier both in drug-free and in drug-containing films, depending on the storage time and the drug content. These obviously cause irregularities in the release of the active ingredient clenbuterol. If the emulsifier is removed from the freeze-dried copolymer by washing with water, a uniform, albeit slow, release of active ingredient is observed in the purified copolymer.

DE-A 195 03 099 describes a process for the preparation of aqueous polymer dispersions by the free-radical aqueous emulsion polymerization method in the presence of a nonionic emulsifier. Suitable nonionic emulsifiers are those whose cloud point is below the polymerization temperature. A variety of suitable compounds are listed, including also nonylphenol emulsifiers.

Task and solution

It was seen as an object to improve dispersions of the prior art, containing methacrylate copolymers with little or no proportions, of monomers with ionic radicals in such a way that, while maintaining the stability of the dispersion and its particle size distribution, drug formulations can be produced therefrom, in which a Phase separation with formation of crystal structures by the emulsifier is omitted. The drug release characteristics and other z. B. mechanical properties can not be changed to the disadvantage.

The task was solved by a

Dispersion, suitable for use as a coating and binder for pharmaceutical forms, with a solids content of 10 - 70 wt .-% consisting of

a) 90 to 99 wt .-% of a methacrylate copolymer which consists of at least 90 wt .-% of (meth) acrylate monomers with neutral residues and a glass transition temperature Tg of - 25 ° C to + 20 ° C determined the DSC method (ISO 1 1357) and

b) 1-10% by weight of a nonionic emulsifier with an HLB value of 15.7 to 16.2.

Implementation of the invention

Methacrylate Copolymer

The dispersion according to the invention contains 90-99% by weight, based on the solids content of a methacrylate copolymer.

The methacrylate copolymer consists of at least 90, in particular 95, preferably 97, in particular 99, particularly preferably 100% by weight of (meth) acrylate monomers with neutral residues, in particular d-bid C - alkyl residues. Suitable monomers are e.g. B. methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate. Methyl methacrylate, ethyl acrylate and methyl acrylate are preferred.

In small proportions, at most 10, preferably at most 5, particularly preferably at most 3 or at most 1% by weight, methacrylate monomers with anionic radicals, for. As methacrylic acid may be included.

The methacrylate copolymer has a glass transition temperature Tg of - 25 ° C to + 20 ° C, preferably - 10 ° C to 0 ° C, determined by the DSC method (ISO 11357).

A typical methacrylate copolymer can e.g. B. from 25 - 35 wt .-% methyl methacrylate and 75 to 65 wt .-% ethyl acrylate.

According to the invention, the per se neutral polymers can contain small amounts of methacrylic acid, which practically do not change the water-insolubility of the polymer, but can influence the swelling and allow pH-dependent control of the permeability.

emulsifiers

The dispersion according to the invention contains 1 to 10, preferably 2 to 8, particularly preferably 4 to 6% by weight, based on the solids content of a nonionic emulsifier with an HLB value of 15.7 to 16.2.

Emulsifiers control the course of the emulsion polymerization process by allowing the chain-building reaction of the emulsified monomers in the water phase. They are therefore an auxiliary necessary for the production and determining the properties of the dispersion. They cannot usually be replaced without fundamentally changing the relevant properties of the dispersion.

The HLB value is a measure of the hydrophilicity or lipophilicity of nonionic surfactants introduced by Griffin in 1950. It can be determined experimentally using the Marszall phenol titration method; see. "Perfumes, Cosmetics", Volume 60, 1979, pp. 444-448; further references in Römpp, Chemie-Lexikon, δ.Aufl. 1983, p.1750. See also z. B. U.S. 4,795,643 (Seth)).

An HLB value (hydrophilic / lipophilic balance) can only be exactly determined with non-ionic emulsifiers. In the case of anionic emulsifiers, this value can be determined by calculation, but is practically always above or well above 20.

The HLB values of the emulsifiers have a significant influence on the crystallization of the emulsifier. Ideally, these values are between 15, 7 and 16.2. After drying, the emulsifiers crystallize above the claimed range. Emulsifiers with an HLB value below the claimed range cannot do the dispersion stabilize sufficiently what can be recognized by strong coagulum formation. The HLB values were either taken from the literature (Fiedler: Lexicon of auxiliary substances) or according to WC Griffin (special print from perfumery and cosmetics 64, 311-314, 316 (1983); Hüthig Verlag, Heidelberg / Pharmind Ind. 60 No. 1 ( 1998); dielectric thermal analysis).

The emulsifier should be toxicologically safe and therefore preferably non-ionic emulsifiers.

Suitable emulsifier classes are ethoxylated fatty acid esters or ethers, ethoxylated sorbitan ethers, ethoxylated alkylphenols, glycerol or sugar esters or wax derivatives

Suitable emulsifiers are, for example, polyoxyethylene glycerol monolaurate, polyoxyethylene glycerol monostearate, polyoxyethylene-20-cetyl stearate, polyoxyethylene-25-cetyl stearate, polyoxyethylene (25) oxypropylene monostearate, polyoxyethylene-20-sorbitan monopalmitate, polyoxyethylene-16-tert.oylylphenol monocetyl ether, ethoxylated castor oil, polyoxyethylene sorbitol wool wax derivatives, polyoxyethylene (25) propylene glycol stearate and polyoxyethylene sorbitol ester

Polyoxyethylene 25 cetyl stearate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 16 tert.octylphenol and polyoxyethylene 20 cetyl ether are preferred. Preparation of the dispersion

The new dispersion is obtained in a manner known per se by aqueous emulsion polymerization in a batch or feed process, semi-continuously or continuously (see, for example, DE 195 03 099 A1).

The radical polymerization of the monomers in the presence of the emulsifier takes place by means of radical-forming, water-soluble polymerization initiators, in which the radical formation can take place thermally or via redox processes. If necessary, molecular weight regulators are added to adjust the molecular weights. Emulsion polymers are usually produced in concentrations between 10 and 70% by weight. A solids content of 30-50% by weight is favorable. Batch production is usually carried out in stirred tank reactors.

For the preparation, in a simple batch production, all monomers according to the desired copolymer composition, together with the emulsifier, initiators, regulators and other auxiliaries, are placed in a reaction kettle together with water and dissolved or dispersed therein. The polymer chain reaction is initiated and carried out by activating the starter (increasing the temperature, adding the redox agent). The known latex particles consisting of polymer chains are formed here.

Antifoam emulsion and stabilizers can be added to the dispersion. uses

The new coating compositions can be processed in a similar manner to other known aqueous acrylate-based coating compositions. The most common are coatings on 0.1 to 3 mm particles after

Fluidized bed process. Usual additives, such as pigments, fillers,

Thickeners, defoamers, preservatives, etc. can be used in common amounts.

Coatings can be created on tablets, capsules, dragees, granules or crystals. The formation of matrix tablets or granules is also possible. Preferred processing temperatures are in the range from 20 to

40 ° C. Suitable film thicknesses are 10 to 80 microns.

According to the mechanism of drug delivery through diffusion, the coating film can be used not only in the gastrointestinal tract, but also in other body cavities, tissues, blood vessels and the habitats of animals and plants, in order to bring about a delayed release of drugs there. Examples are films that are inserted into the bloodstream with catheters, implants of veterinary drugs.

As with other aqueous coating media, layers of multi-layer coating systems can be created. For example, a core that contains, for example, basic or water-sensitive active ingredients, can be provided with an insulating layer made of another coating material, such as cellulose ethers, cellulose esters, cationic polymethacrylates (such as EUDRAGIT ^® E I00, -RL 100, RS 100, Röhm GmbH), before the coating agent according to the invention is applied. Likewise, further coatings can then be applied, for example with an odor or taste-masking effect or with an appealing coloring or gloss effect. The release characteristics of drug coatings in vitro are usually tested according to USP with artificial gastric juice (0.1 N HCI) and artificial intestinal juice (pH 6.8).

Further applications are described in the following literature:

Bauer, Lehmann, Osterwald, Rothgang: Coated Dosage Forms, CRC Press

LLC, Boca Raton, Florida, Medpharm Scientific Publishers, Stuttgart 1998

I. Ghebre-Sellassie, Multiparticulate Oral Drug Delivery, Marcel Dekker, Inc. New York, Basel, Hong Kong, 1994

Spray jobs from mixtures with other dispersions:

K. Lehmann, D. Dreher: Mixtures of Aqueous Polymethacrylate Dispersions for

Drug coating, drugs made in Germany 31 101-102 (1988)

Matrix tablets over wet granulation

K. Lehmann, H.-U. Petereit, use of aqueous poly (meth) acrylate

Dispersions for the production of matrix tablets, Acta Pharm. Technol.

34 (4) 189-195 (1988)

J. McGinity, Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, ^2nd Edition, Marcel Dekker, Inc. New York, Basel, Hong Kong, 1996

Decaying prolonged-release tablets

K. Lehmann, H.-U. Petereit, D. Dreher, Rapidly Disintegrating Tablets with Controlled Release of Active Ingredients, Pharm. Ind. 55, (10) 940-947 (1993) K. Lehmann, H.-U. Petereit, D. Dreher, Fast Disintegrating Controlled Release Tablets from Coated Particles, Drug Made in Germany 37 (2), 53-60 (1994) R. Bodmeier, Tabletting of Coated Pellets Eur. J.Phar and Biopharm. 43 1-8 (1997)

(Trans) dermal therapy systems

- Heilmann, K.: Therapeutische Systeme, Ferdinand Euler Verlag, Stuttgart, pp. 52-57.

- Brandau, R. and Lippold, B.H. (1982): Dermal and Transdermal Absorption. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, pp. 171 - 200.

H.-U. Pete Riding, 3 ^rd European Congress of Biopharmaceutics and Pharmacokinetics-Proceed. Vol. I, 84-93 (1987)

Use of the solid:

The solid obtained from the dispersions according to the invention by drying, coagulation or squeezing extrusion can be used as follows:

Extrusion: If necessary after mixing with auxiliaries and / or active ingredients to form granules, films and. etc. ..

Injection molding: According to the new injection molding application for hollow bodies and monolithic supports

Dissolution: The polymer is soluble in common solvents such as short-chain alcohols or ketones. Such solutions can be used in conventional coating processes. Advantageous effects of the invention

The dispersions according to the invention are used as binders and binders in pharmaceutical production. Primarily, the physico-chemical properties necessary for this effect must be achieved (see examples 4 and 5). In particular, reliable film formation at temperatures below 10 ° C. is advantageous, so that processing without the addition of plasticizer is possible. The reproducible coalescence of the latex particles allows the formulation of sustained-release medicinal products.

If the crystallization of emulsifiers described above occurs, it represents a considerable deterioration in the quality of medicinal products. In terms of pharmaceutical safety, the emulsifiers should therefore not crystallize out after drying. This effect is obviously achieved through the structure-related interaction of the emulsifier with the polymer. The dispersions according to the invention thus allow the development of more reliable sustained-release medicinal products.

The invention is particularly suitable for the provision of pharmaceutical forms containing the active ingredients below.

Therapeutic categories:

Analgesics, anti-rheumatic drugs, anti-allergies, anti-arrhythmic drugs, beta-blockers, calcium channel blockers, inhibitors of the renin-angiotensin system, broncholytics / anti-asthmatics, cholinergics, diuretics, blood circulation stimulants, gout medicines, fluids, coronary drugs, lipid-lowering agents, gastrointestinal drugs, psychiatric drugs Antiplatelet agents Urologics Venetherapeutics Vitamins and minerals

drugs

Morphine and its derivatives, tramadol, acetylsalicylic acid, diclofenac, indomethacin, lonazolac, ibuprofen, ketoprofen, propyphenazone, naproxen, paracetamol, flurbiprofen, dimetindene, quinidine, metoprolol, propranolol, oxprenolol, pololololololololololololololololololololololololololololololololololololololololololololololol -ol-dol-ol-dol-ol-ol-p-dol-ol-ol-p-dol-ol-ol-dol-ol-olipolol , nifedipine, nicardipine, nisoldipine, nimodipine, amlodipine, theophylline, salbutamol, terbutaline, ambroxol, aminophylline, choline, pyridostigmine, piretanide, furosemide, pentoxifylline, naftidrofuryl, buflomedil, xanthinol nicotinate, bencyclane, allopurinol, norephedrine, Clorphenamin isosorbide mononitrate, isosorbide dinitrate, Giyceroltrinitrat, Molsidomine, bezafibrate, fenofibrate, gemfibrozil, cerivastatin, pravastatin, fluvastatin, lovastatin, atorvastatin, simvastatin, xantinol, metoclopramide, amitriptyline, dibenzepine, venlafaxine, thioridazine, oxazepam, lithium, nitroforbic acid and pharmaceuticals used, and salicofurium acid and herbal drugs.

EXAMPLES

Test Methods

Solids content: 1 g of dispersion is dried in an oven for 3 hours at 110 ° C. according to Pharm. Eur. 2.2.32 method d. pH value: determined according to Pharm. Eur. Method 2.2.3. Dynamic viscosity: Determined with a Brookfield viscometer (UL

Adapter / 30 min ^" 1/20 ° C)

Particle size: determined from dilute dispersion using a Nanosizer (Fa.

Coulter).

Coagulum content: Via a precisely weighed sieve with a mesh size of 0.09 mm

(mesh no. 90, ISO) 100 g of dispersion are added and cleaned with

Wash water until the run is clear. Sieve and residue are dried to constant weight at 105 ° C and weighed precisely. The

Weight difference is calculated as% of the examined amount of dispersion.

Crystallization of the emulsifier:

Approx. 0.3 g dispersion is placed on a slide and dried at <10 ° C for at least 12 h. The crystallization of the emulsifier in the dried film is then checked under a polarizing microscope at 400 × magnification. The crystal formation can be seen from the colored light birefringence, amorphous areas can be seen dark.

1st - 5th variation of the polymer composition

To prepare the dispersion, 55.0 kg of water are placed in a reaction kettle and 328 g of polyoxyethylene-20-cetyl ether are dissolved therein. After the dissolving process, the monomers according to Table 6.6 kg of ethyl acrylate, 7.1 kg of methyl methacrylate and 0.3 kg of methacrylic acid are added and emulsified at 30 ° C.

To start the reaction, the water-soluble initiators (0.22 g iron (II) sulfate dissolved in 160 g water, 22.0 g ammonium peroxodisulfate and 30.8 g sodium disulfite, each dissolved in 320 g water) are added. To The batch is cooled when the temperature peak is reached. At approx. 50 ° C, 754g emulsifier are added according to the table for post-stabilization. After reaching 40 ° C., 6.7 g of ammonium peroxodisulfate, dissolved in 160 g of water, are added for the after-reaction, and the dispersion is filtered and then deodorized.

6-15. Variation of the emulsifier

To prepare the dispersion, 55.0 kg of water are placed in a reaction kettle and 328 g of emulsifier are dissolved therein in accordance with the table. After the dissolving process, 16.6 kg of ethyl acrylate, 7.1 kg of methyl methacrylate and 0.3 kg of methacrylic acid are added and emulsified at 30 ° C. To start the reaction, the water-soluble initiators (0.22 g iron (II) sulfate dissolved in 160 g water, 22.0 g ammonium peroxodisulfate and 30.8 g sodium disulfite, each dissolved in 320 g water) are added. After the temperature peak has been reached, the batch is cooled. At approx. 50 ° C 754 g of emulsifier according to the table are added for post-stabilization. After reaching 40 ° C., 6.7 g of ammonium peroxodisulfate, dissolved in 160 g of water, are added for the after-reaction, and the dispersion is filtered and then deodorized.

because of coagulation

16.- 18 variation of the manufacturing process

16. Dispersion production via emulsion polymerization in a one-step batch process

To prepare the dispersion, 55.0 kg of water are placed in a reaction kettle and 328 g of polyoxyethylene-20-cetyl ether are dissolved therein in accordance with the table. After the dissolving process, 16.6 kg of ethyl acrylate, 7.1 kg of methyl methacrylate and 0.3 kg of methacrylic acid are added and emulsified at 30 ° C.

To start the reaction, the water-soluble initiators (0.22 g iron (II) sulfate dissolved in 160 g water, 22.0 g ammonium peroxodisulfate and 30.8 g sodium disulfite, each dissolved in 320 g water) are added. After the temperature peak has been reached, the batch is cooled. At approx. 50 ° C, 754g emulsifier are added according to the table for post-stabilization. After reaching 40 ° C., 6.7 g of ammonium peroxodisulfate, dissolved in 160 g of water, are added for the after-reaction, and the dispersion is filtered and then deodorized.

17. Dispersion preparation Dispersion via emulsion polymerization in a double batch process

For the first batch of the dispersion, 23.0 kg of water are placed in a reaction kettle and 512 g of emulsifier are dissolved therein in accordance with the table. After the dissolving process, 8.30 kg of ethyl acrylate, 3.55 kg of methyl methacrylate and 0.14 kg of methacrylic acid are added and emulsified at 30 ° C. To start the reaction, the water-soluble initiators (0.22 g iron (II) sulfate, 11.0 g ammonium peroxodisulfate and 15.4 g sodium disulfite, each dissolved in 160g water) added. After reaching the temperature peak, the batch is cooled to 50 ° C.

For the 2nd batch, 570g emulsifier are added to the 1st batch and the mixture is stirred for 30 minutes. The same amount of monomers is then added analogously to the first batch, the mixture is stirred for 10 minutes and the initiators (11.0 g ammonium peroxodisulfate and 15.4 g sodium disulfite, each dissolved in 160 g water) are added. After the end of the reaction, the batch is cooled to 40 ° C. and initiator (6.7 g ammonium peroxodisulfate, dissolved in 160 g water) is added for the after-reaction. For deodorization, the dispersion is adjusted to a pH of about 8 in a reaction kettle with dilute sodium hydroxide solution and 10-15% of the water of dispersion is distilled off. The dispersion is then diluted to a solids content of approximately 30%. The dispersion is then filtered.

18. Dispersion production Dispersion via emulsion polymerization in the feed process

In a glass reactor, 2370 g of water and 5.0 g of emulsifier according to the table are heated to 80 ° C. with stirring. In the meantime, a pre-emulsion consisting of 1800 g of water, 64.9 g of emulsifier, 3.0 g of ammonium peroxodisulfate, 1245.6 g of ethyl acrylate, 532.8 g of methyl methacrylate and 21.6 g of methacrylic acid is produced using a high-shear stirrer. The amount of initiator provided for starting the reaction (1.2 g of ammonium peroxodisulfate, dissolved in 30 g of water) is added to the initial charge and the pre-emulsion is metered into the initial charge at 80 ° C. within four hours. After the end of the feed, the resulting dispersion is stirred for a further two hours at 80 ° C., then cooled to room temperature and adjusted to a pH of about 8 with dilute sodium hydroxide solution and 10-15% of the Dispersed water of distillation. The dispersion is then diluted to a solids content of approximately 30%. The dispersion is then filtered.

The dispersion obtained was tested for the properties given in the table. The table shows the analytical values of the dispersions according to the production conditions mentioned above.

19. Use of the dispersion as a coating agent:

a) Coatings on potassium chloride crystals.

In a fluidized bed device (GPCG 1, from GLATT), 800 g of KCI crystals (0.3-0.8 mm) with a spray suspension of 373.3 g of the dispersion according to the invention according to Example 12, 112 g of talc, 0.95 g of antifoam emulsion and 412 g of purified water coated. The supply air temperature is 30 ° C and the spray pressure at the nozzle (diameter 1.2 mm) is 2.0 bar. The spraying time is approx. 90 min. After drying at room temperature for 16 hours, uniform coated crystals are obtained.

The release of the potassium chloride crystals was measured over 6 hours in a paddle device at 100 rpm in 900 ml of water. The potassium chloride content was determined potentiometrically. The release profile of the potassium chloride crystals coated with the dispersion according to the invention shows a uniform retardation over 6 hours (see Figure 1/2).

20. Use of the dispersion as a binder:

Matrix tablets with a total mass of 600 mg and a diprophylline content of 150 mg are produced. For 1.2 kg of matrix tablets, 300 g of diprophylline are mixed with 400 g of calcium hydrogenphosphate dihydrate (0.1-0.2 mm) in the STEPHAN UM 12 and then moistened with the dispersion according to Example 12 according to the invention. After drying at 40 ° C for 6 hours, the tablet mass is passed through a 1 mm sieve, mixed with 12 g magnesium stearate and pressed on a KORSCH eccentric tablet press with 10 kN. The resulting tablets shine slightly, have good mechanical strength and show a uniform release rate over 6-7 hours.

The release profile of the matrix tablets with diprophylline also shows an even retraction (Figure 2/2). The drug release was determined over 6 hours in a paddle device at 50 rpm in 900 ml water with a UV-VIS spectrometer Perkin-Elmer Lambda 20 at 274 nm.

Claims

1. Dispersion, suitable for use as a coating and binder for pharmaceutical forms, with a solids content of 10 - 70 wt .-% consisting of

a) 90 to 99% by weight of a methacrylate copolymer which consists of at least 90% by weight of (meth) acrylate monomers with neutral residues and has a glass transition temperature Tg of from −20 ° C. to + 20 ° C. the DSC method and

b) 1-10% by weight of a nonionic emulsifier with an HLB value of 15.2 to 17.3.

2. Dispersion according to claim 1, characterized in that the methacrylate copolymer consists of 20 to 50 wt .-% of methyl methacrylate, 80 to 50 wt .-% ethyl acrylate and optionally 0 to 10 wt .-% methacrylic acid.

3. Dispersion according to claim 1 or 2, characterized in that the nonionic emulsifier is selected from the group of substances of ethoxylated fatty acid esters or ethers, ethoxylated sorbitan ethers, ethoxylated alkylphenols, glycerol or sugar esters or wax derivatives.

REPLACEMENT SHEET RULE 26

4. Dispersion according to one or more of claims 1 to 3, characterized in that the nonionic emulsifier is selected from the group polyoxyethylene glycerol monolaurate,

Polyoxyethylene glycerol monostearate, polyoxyethylene-20-cetyl stearate polyoxyethylene-25-cetyl stearate, polyoxyethylene (25) oxypropylene monostearate, polyoxyethylene-20-sorbitan monopalmitate, polyoxyethylene-16-tert.octylphenol, polyoxyethylene-20-cetylether, polyocetylene ethoxylate, polyethylenetlycolethylene (1000) ethylenetlycolethylene (1000) ethoxylated glycol (1000) Wool wax derivatives, polyoxyethylene (25) propylene glycol stearate, polyoxyethylene sorbitol ester, polyoxyethylene 25 cetyl stearate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 16 tert-octylphenol and polyoxyethylene 20 cetyl ether

5. A process for the preparation of a dispersion according to one or more of claims 1 to 4 in a manner known per se by emulsion polymerization.

6. Use of a dispersion according to one or more of claims 1 to 4 as a coating or binder for the manufacture of medicaments.

REPLACEMENT BLADE (RULE 26)

7. Use according to claim 6, characterized in that the coated or bound medicament is one of the active ingredients morphine and its derivatives. Metoprolol, propranolol, oxprenolol, pindolol, atenolol, metoprolol, disopyramide, verapamil, diltiazem, gallopamil, nifedipine, nicardipine, nisoldipine, nimodipine, amiodipine, theophylline, piridolidolidol, pyridolinolinolidylolololinolidolololinolylolololinolylolololinolylolololinolylolololinolylolololinolylolololinolylolololinolylolololinolylololololylololololylolololylolololylolololylolololylololylolololylolololylolidololylololylolidylololylolylolylolylolylolidylolylolidylolylolylolylolylolide naftidrofuryl, buflomedil, xanthinol nicotinate, bencyclane, allopurinol, norephedrine, Clorphenamin isosorbide mononitrate, isosorbide dinitrate, glycerol trinitrate, molsidomine, bezafibrate, fenofibrate, gemfibrozil, cerivastatin, pravastatin, fluvastatin, lovastatin, atorvastatin, simvastatin, Xantinol, metoclopramide, amitriptyline, dibenzepin, venlafaxine, thioridazine , Oxazepam, lithi um, contain nitrofurantoin, vegetable dry extract, ascorbic acid and potassium and their pharmaceutically used salts.

8. Dosage form containing a pharmaceutical active ingredient, characterized in that the active ingredient is bound or coated with an emulsion polymer, which was obtained from a dispersion according to one or more of claims 1 to 5 by drying.

REPLACEMENT BLADE (RULE 26)